http://dx.doi.org/10.4110/in.2012.12.4.129 RIEVIEW ARTICLE pISSN 1598-2629 eISSN 2092-6685

Immune Disorders and Its Correlation with Gut Microbiome

† † Ji-Sun Hwang1 , Chang-Rok Im2 and Sin-Hyeog Im1* 1School of Life Sciences and Immune Synapse Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, 2Global Leader Program, Bugil Academy, Cheonan 330-941, Korea

Allergic disorders such as atopic and are also exert beneficial effects by directly modulating immune common hyper-immune disorders in industrialized countries. system. For example, an oral treatment of certain Along with genetic association, environmental factors and or a mixture of them prevented and improved symptoms of have been suggested as major triggering fac- experimental inflammatory bowel disease, tors for the development of atopic dermatitis. Numerous and asthma by down-regulating inflammatory cytokines or in- studies support the association of hypothesis in al- ducing immune regulatory mechanisms. However, these ben- lergic immune disorders that a lack of early childhood ex- eficial effects are strain-specific (2-4), suggesting the necessity posure to diverse microorganism increases susceptibility to of development of screening system to identify specific pro- allergic diseases. Among the symbiotic microorganisms (e.g. gut flora or probiotics), probiotics confer health benefits biotics to treat specific disorders. through multiple action mechanisms including modification of Atopic dermatitis (AD) is chronic, relapsing inflammatory immune response in gut associated lymphoid tissue (GALT). skin disorder and a complex immune response mediated by Although many human clinical trials and mouse studies dem- genetic, environment factors and skin barrier dysfunction. onstrated the beneficial effects of probiotics in diverse im- Recently, the incidence of atopic dermatitis has remarkably mune disorders, this effect is strain specific and needs to ap- increased especially in the industrial cities compared to rural ply specific probiotics for specific allergic diseases. Herein, areas and developing countries, which strongly support the we briefly review the diverse functions and regulation mecha- “hygiene hypothesis” in the development of allergic immune nisms of probiotics in diverse disorders. disorders (5,6). Hygiene hypothesis has received worldwide at- [Immune Network 2012;12(4):129-138] tention from many scientists as the subject remains questioned for many years. Hygiene hypothesis states that a lack of early INTRODUCTION childhood exposure to infectious agents, symbiotic micro- organisms (e.g. gut flora or probiotics), and parasites increases “Probiotics” are defined as live microorganisms that, when susceptibility to allergic diseases by suppressing natural devel- administered in adequate amounts, confer a health benefit on opment of the (7). Even though treatment the host (1). Although the beneficial effect of probiotics ad- with corticosteroid is the most well used method to treat atop- ministration was mainly known to improve the balance of in- ic dermatitis, long term usage of steroid can cause many side testinal microflora, recent studies showed that probiotics can effects including the atrophoderma and growth retardation

Received on July 7, 2012. Revised on July 19, 2012. Accepted on July 27, 2012. CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribu- tion, and reproduction in any medium, provided the original work is properly cited. *Corresponding Author. Tel: 82-62-715-2503; Fax: 82-62-715-2484; E-mail: [email protected] †These authors contributed equally to this work.

Keywords: Hygiene hypothesis, Intestinal microflora, Gut-Associated lymphoid tissue, Probiotics, Atopic dermatitis

Abbreviations: GALT, Gut-Associated Lymphoid Tissue; GI, Gastrointestinal; MLN, Messenteric Lymph Node; AD, Atopic Dermatitis; HMP, Human Microbiome Project; IBD, Inflammatory Bowel Disease; T1D, ; DC, Dendritic Cell; NOD, Nucleotide-binding Oligomerization Domain; TLT, Toll-Like Rceptor; Treg, Regulatory T Cells; iDO, Indoleamine 2,3-dioxygenase; SCORD, SCORing Atopic Dermatitis

IMMUNE NETWORK www.immunenetwork.org Volume 12 Number 4 August 2012 129 Immune Disorders and Its Correlation with Gut Microbiome Ji-Sun Hwang, et al.

(8). So many studies were focused on the development of ities and forty people inhibiting in cities by metagenomic innovative prevention and treatment strategies for AD to re- analysis, scientists discovered that the distribution of intestinal place the steroid treatment. Interestingly, recent studies also of the two groups has a stark contrast. Surprisingly, suggest the association of dysregulation of gut microbiota it was found that those living in rural habitats have about with diverse diseases including atopic dermatitis (9). There- three to five times more Lactobacillus acidophilus (LA). LA fore manipulation of the intestinal flora with good probiotics metabolizes lactic acid, obtains vitamin K, a cofactor for will be complementary and alternative treatments to divert blood clotting and healthy bone tissue turnover. LA also helps immune response from the hyper-immune states. In this re- recycle the amino acids in bile, and normalizes the body’s view, we summarized the hygiene hypothesis and its correla- cholesterol level compared to people living in cities. Possible tion with gut microbiome, especially on the aspect of pro- explanations to this phenomenon are attributing to the level biotics, in the development and regulation mechanisms of di- of stress and the difference in abiotic factors such as air and verse disorders. water and life span or health of people. Most importantly, distribution of helpful microorganisms is mainly derived from Microbiome and its relevance to the susceptibility of the types of foods consumed (19,20). The potential roles of diverse diseases microbiome on diverse disorders are summarized below. Several hypotheses have been proposed as the cause of de- Atopic dermatitis: Studies investigating the composition velopment in allergic disease, including atopic dermatitis. of the intestinal microflora in humans have shown the pivotal Among them, “hygiene hypothesis” has gained the most atten- role of commensal bacteria in the development of . tions (7). This hypothesis explains that early childhood Studies comparing the microflora composition of atopic and caused by unhygienic contact with older siblings could prevent non-atopic infants also show significant differences. Non- the development of allergic disease (10). Later, Th1/Th2 para- atopic infants have more colonization of Bifidobacteria and digm was added that a lack of early childhood infection re- Lactobacillus in the intestine while there is much colonization sults a decreased Th1 immune response, which disturbs the of Clostridia in the intestine of atopic infants. However sev- Th1/Th2 balance and leads to an abundant Th2 response, eral reports also suggest that there are no significant differ- causing allergic disease (11). Later this hypothesis was further ences between the two groups (21,22). The exact role of in- revised, which considers changes in the intestinal colonization testinal flora in the development of atopic disease in the pattern during infancy and overlay hygienic lifestyle as the childhood is still not clarified (23). In addition to these quan- most important reasons for the increased prevalence. titative differences in the Bifidobacterium, qualitative differ- Especially overlay hygiene can induce a lack of activity of ences have also been observed. The Bifidobacteria from atop- regulatory T cells, causing over-activation of Th1 as well as ic infants were found to induce much higher levels of pro-in- Th2 responses as the underlying mechanism of allergic disease flammatory cytokines in vitro whereas the Bifidobacteria from (12,13). non-atopic infants induced more secretion of anti-inflamma- As explained by hygiene hypothesis, a person’s life span tory cytokines. In addition to different secretion ability, differ- is largely affected by the distribution of intestinal bacteria. ential adhesion to intestinal mucosa may also result in a dif- The term “microbiome” was coined by Joshua Lederberg, ferent or reduced stimulation of the immune system through who argued that microorganisms inhabiting the human body the gut-associated lymphoid tissue (GALT) (24). should be included as part of the human genome, because Obesity: Obesity is associated with the changes in the rel- of their influence on human physiology and the human body ative abundance of the two dominant bacterial divisions, the contains over 10 times more microbial cells than human cells Bacteroids and the Firmicutes. The relative proportion of (14,15). To understand the microbiome (totality of microbes) Bacteroids is decreased in obese people compared to lean and the factors that influence the distribution and evolution people while the proportion of Firmicutes is increased in of the constituent microorganisms, the Human Microbiome obese people. Obese microbiome has an increased capacity Project (HMP) was initiated. HMP has aimed to identify and to harvest energy from the diet and colonization of germ-free characterize the microorganisms which are found in associa- mice with an obese microbiota results in greater increase in tion with both healthy and diseased human (16-18). After in- total body fat without any increase in food consumption than vestigating the feces of forty people living in rural commun- colonization with a lean microbiota (25-27).

130 IMMUNE NETWORK www.immunenetwork.org Volume 12 Number 4 August 2012 Immune Disorders and Its Correlation with Gut Microbiome Ji-Sun Hwang, et al.

Type 1 diabetes (T1D): Metagenomic analysis revealed propria can capture directly by dendrites (35-37). the close relatedness of bacteria with the development of T1D Intestinal microflora seems to be involved in the induction of associated in young child. Especially the pro- oral tolerance which is established in the periphery to specific portion of Bacteroides ovatus was increased in children with after ingestion of orally delivered protein (antigen) T1D while the proportion of Firmicutes, CO19 was increased and plays a pivotal role in the induction and maintenance of in normal healthy children (28). peripheral tolerance mediated by regulatory T cells (38,39). All these results collectively imply that gut microbiota Skin microflora: Most studies delineating the role of resi- could be an additional contributing factor to the pathophysiol- dent microorganisms in regulation of immune system and in- ogy of obesity, T1D as well as atopic dermatitis, which in flammation have focused on the gut microbiome, since gut turn suggest that bacterial markers can be used for early diag- is the main site of exposure and contains a wide diversity nosis for these disorders. In addition, supplementation of of microbes. However, skin was considered to just have a large amount of bacteria that negatively correlated with the physical barrier function to protect our body from the attack of disease state may be beneficial for the prevention of these pathogens. Interestingly recent studies discovered that skin mi- disorders. crobiome also have similar function that of gut microbiome (40). Microbial profiling by metagenomic analysis has revealed the Microflora and immune system presence of highly diverse commensal communities in skin The intestinal microflora: Based on the hygiene hypoth- sites (41). Moreover, cutaneous inflammatory disorders, such esis, in addition to environmental factors, the intestinal micro- as psoriasis and atopic dermatitis have been associated with flora is another contributor to allergic disease by substantially imbalance of the cutaneous microbiota (42,43). Indeed, mi- affecting the mucosal immunity. Allergic responses are crobial products from skin commensals are known to exert thought to arise if there is absence of microbial exposure immunoregulatory effects (44). Yasmine Belkaid group re- while the immune system is developing (24,29). The gastro- ported that the roles for the skin microbiota in controlling the intestinal tract is an important interface between host and en- local inflammatory milieu. They showed that protective im- vironment and has the dual role of facilitating the absorption munity to a cutaneous pathogen is critically dependent on the of nutrients while excluding pathogens. The human intestines skin but not on gut microbiota (45). Furthermore, skin com- are inhabited by at least 400 different bacterial species, with mensals activate the function of local T cells through the in- the greatest density in the large intestine, where concentration terleukin-1 receptor (IL-1R)-MyD88 signaling pathway (45). of 1011-1012 cells/g of luminal contents can be found (30). These findings indicate the critical role of the skin residual Because a large part of the intestinal microflora cannot be commensal bacteria not only as a distinctive feature of tissue cultured with current culture techniques, it has been sug- compartmentalization also as a key regulator of the immune gested that the number of microflora species in the human system in health and disease. intestine may exceed 1,000 species (24). Although some in- testinal bacteria are potential pathogens, the relationship be- Action mechanisms of probiotics tween the intestinal microflora and the human host is mostly General regulation mechanisms in gut: The intestinal symbiotic in healthy individuals. commensal bacteria play diverse functions in regulating nu- Gut-Associated Lymphoid Tissue (GALT): The largest trient metabolism including absorption of indigestible carbo- mass of lymphoid tissue of the human body can be found hydrate and production of short chain fatty acid, amino acid in the gastrointestinal tract and is called as the gut- associated and vitamin. Microflora provides additional energy by digest- lymphoid tissue (GALT) which includes Peyer's patch and ing exogenous and endogenous substrates, such as fibers and mesenteric lymph node (MLN) (31). GALT interact with in- mucins. Microflora also provide a protective barrier against testinal bacteria which are sampled by dendritic cells (DCs) incoming bacteria (46). This protection is mediated by several and intestinal epithelial cells through the pattern recognition different mechanisms including competition for nutrients and receptors such as toll-like receptor (TLR) and nucleotide-bind- binding sites and production of antimicrobial substances (37,47). ing oligomerization domain (NOD) (32-34). The intestinal an- Immune regulation mechanism: Probiotics could stim- tigens also can be captured by DCs in the Peyer's patch ulate the immune system by modulating the composition through M cells on the surface of enterocytes. DCs in lamina and/or activity of the intestinal microbiota (48,49). The im-

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munomodulatory role of probiotics has been shown in di- (54-56). Recently we have demonstrated that administration verse types of inflammatory immune disorders both, in gas- of IRT5 probiotics mixture increases the generation of trointestinal diseases and in non-gastrointestinal diseases. The CD4+Foxp3+ Tregs in the mesenteric lymph nodes (MLN) beneficial effect of probiotics is strain-specific and their effec- through the generation of CD11c+ regulatory dendritic cells tor mechanisms are also quite diverse. Some probiotics gen- (rDCs) that highly express high levels of IL-10, TGF-β and erate IL-10 producing Tr1 or CD4+Foxp3+ Treg cells (50), indoleamine 2,3-dioxygenase (iDO) (52), which in turn while others could enhance immunity by producing a large potentiated the generation of CD4+Foxp3+ Tregs from the amount of IL-1β, IL-12 or TNF-α (51). For example Lactoba- pool of CD4+CD25- cells. These results suggest that probiotics cillus reuteri induces the production of IL-12 and TNF-αfrom or a mixture of them that can induce regulatory DCs in the DCs while Lactobacillus casei inhibits the production of MLN, which in turn induce the production of CD4+Foxp3+ pro-inflammatory cytokines by producing anti-inflammatory cells, could represent an attractive potential therapy for the cytokines such as IL-10. Therefore it is crucial to use specific treatment of diverse inflammatory immune disorders. probiotics or their mixture to target specific immune disor- The role of probiotics in atopic dermatitis: Atopic der- ders. Most of the allergic diseases are associated with a shift matitis (AD) is caused by diverse pathogenic factors including of the Th1/Th2 balance toward a Th2 response, which in- genetic susceptibility, environment trigger, skin barrier dys- duces secretion of Th2 type cytokines such as IL-4, IL-5 and function, bacterial infection and (5). IL-13 leading to higher production of IgE. Recently, we have AD is a complex immune reaction mediated by both Th1 and demonstrated that IRT5 probiotics, a mixture of 5 probiotics, Th2 immune responses (6). Th2 type cytokines including could suppress diverse immune disorders through the gen- IL-4, IL-5 and IL-13 play important role in the development eration of CD4+Foxp3+ Tregs (52). Oral administration of IRT5 of AD by increasing the levels of serum IgE and blood eosi- probiotics generated rDCs (iDOhigh, Cox2high, IL10+, TGFβ+), nophils in AD patients (57). In the later stage of AD where which can convert effector CD4+Foxp3- T cells into CD4+Foxp3+ infection mediated occurs, Th1 type cytokines regulatory T cells in the mucosal immune system. In addition, such as IFN-γand IL-12 mediate chronic stage of atopic der- oral administration of the IRT5 probiotics suppressed ongoing matitis (5,58,59). IFN-γis also involved in the maintenance experimental AD and pathogenesis of experimental arthritis of chronic stage of atopic dermatitis by elevating the ex- as well (52). Currently we are investigating to identify potent pression of CCL17 (TARC) and CCL22 (MDC) that are in- strains that could induce the production of im- volved in the recruitment of effector T cells to the inflamed mune-modulatory cytokines such as IL-10 and TGF-β or en- site (60). IFN-γ increases the sensitivity of Fas-mediated hancing Th1 response to improves the symptoms of allergic apoptosis of keratinocytes, which is considered to be a key disease (37,53). pathogenic event in eczematous dermatitis (61). Based on The effect of probiotics on dendritic cells (DCs): DCs many clinical as well as animal studies, therapeutic or pre- function as a professional antigen presenting cells (APC) and ventive effects of probiotics on allergic disease have been in- have the ability to activated T cells and directly regulate Th1 tensively investigated as summarized hereinafter. and Th2 cell. Especially DCs lead to the induction of regulatory T cells through the secretion of IL-10 and TGF-β 1. Human clinical trials and help to regulate immune response by the production of (1) Prevention: Several randomized controlled trials (RCT) IL-10 from Tr1 cells and TGF-β from Th3 cells. Once DCs have investigated the effect of probiotics on the prevention capture antigens in the presence of proper inflammatory of atopic dermatitis. In these trials probiotics were given to stimuli, they migrate to secondary lymphoid organs and infants with a high risk of developing allergy, starting immedi- simultaneously undergo a maturation process. During this ately after birth and mothers also received probiotics during maturation, DCs produce diverse cytokines and express the last week of pregnancy. The first trial reported that a 50% surface molecules such as MHC, CD40, CD83, CD80 (B7.1) reduction of the incidence of AD in the probiotics group com- and CD81 (B7.2). Recently several reports suggest that pare to placebo group at the age of 2 year and this effect probiotics can induce the maturation and cytokine secretion was maintained until at 7 years (62). A clinical trial reported by DCs. Different probiotics exert differential effect on the that administration of probiotics only reduced the incidence cytokine profiling by DCs such as IL-12, TNF-α and IL-10 of IgE-associated AD without altering other allergic diseases

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(63). In another report, consumption of Lactobacillus rhamno- dermatitis) in the probiotics treated group (67). Other reports sus reduced the incidence of AD while Bifidobacterium ani- showed that probiotics significantly decreased SCORAD of malis did not show any reduction, suggesting the strain de- IgE-associated not general AD (68,69). These reports suggest pendent preventive effect of probiotics (64). In contrast, two that only children who at a young age already have IgE sensi- prevention studies did not show any effect on AD incidence. tization such as elevated total or specific IgE levels get a ben- Moreover one of the studies reported an increased sensitization efit from probiotics administration. However there are also rate for food or aeroallergens in the probiotics group (65,66). several studies that did not show any effect of probiotics on There are several possible explanations for these inconclusive the severity or incidence of atopic dermatitis (70,71). There results. First, different lactobacillus strains were used and this are considerable variations in the probiotic strains and daily indicates that not all strains are effective for atopic dermatitis. dosage and number, age, severity of AD of participants and Second, probiotic effects are dose dependent and there was treatment period, which may result in conflicting results. considerable variation in the daily dosage. The third ex- planation could be a difference in study design such as num- 2. Experimental animal model bers and atopic risk of participants and supplementation of Beneficial effect of probiotics on AD development was eval- the mother during breastfeeding. These studies suggest that uated in the experimental mouse models. We have recently careful consideration much be established to decide which showed that administration of IRT5 probiotics mixture to ex- probiotics or a mixture of them are employed to treat allergic perimental AD mice reduced serum IgE levels and infiltration atopic dermatitis. of lymphocytes to inflamed sites by recruiting CD4+Foxp3+ (2) Treatment: Randomized controlled trials to examine regulatory T cells (52). Administration of Lactobacillus rham- the effect of probiotics in the treatment of atopic dermatitis nosus GG (LGG) to Nc/Nga mice during pregnancy and in child also have inconclusive results. Several studies breastfeeding also delayed onset or incidence of atopic der- showed a significant reduction of SCORAD (SCORing Atopic matitis by increasing IL-10 level in GALT. (72). As a similar

Table I. The role of probiotics in atopic dermatitis Study type Author (reference #) Probiotics Result Human Kalliomäki (62) LGG Decreased atopic dermatitis prevention Abrahamsson (63) L. reuteri Decreased IgE-associated AD not other allergic disorders Wickens (64) L. rhamnosus or -L. rhamnosus group: reduction of AD and Bifidobacterium animalis IgE-associated AD incidence subsplactis -Bifidobacterium group: no effect Kopp (66) LGG No prevention of AD, increased sensitization rate for food or aeroallergens Human Weston (67) L. fermentum Decreased SCORD treatment Viljanen (68) LGG or MIX Decreased IgE-associated SCORD Sistek (69) L. rhamnosus B. lactis Decreased IgE-associated SCORD Fölster-Holst (70) LGG No reduction of severity or incidence of AD Mouse prevention/ Kwon (52) IRT5 (MIX) Reduction of serum IgE, induction of treatment Treg via generation of rDC Sawada (72) LGG Delayed onset or incidence of AD by increasing IL-10 level in GALT Tanaka (73) Lactobacillus Improved AD symptoms by significantly rhamnosus CGMCC decreasing serum IgE levels as well as Th2 type cytokine expression Won (74) Lactobacillus Improved AD symptoms by significantly decreasing serum IgE levels as well as Th2 type cytokine expression while increasing IFN-γ and IL-10 expression

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study, administration of three Lactobacillus strains isolated Probiotics may be capable of recolonizing the bowel with from Kimchi to Nc/Nga mice improved AD symptoms by sig- non-pathogenic strains of bacteria. Probiotics have long been nificantly decreasing serum IgE levels as well as Th2 type cy- shown to be beneficial in both infectious and non-infectious tokine expression while increasing IFN-γ and IL-10 ex- digestive disorders. Growing evidence indicates that pro- pression (73,74). However, it is still unclear on the mecha- biotics may be effective in the treatment of specific clinical nism by which administration of probiotics generates regu- IBD conditions. latory T cell populations. In addition, further studies are re- Although it is unclear whether the abnormal composition quired to identify potent immunoregulatroy probiotics among of the entreric flora contributes to the pathogenesis of IBD, the hundreds of probioctic strains. Recently we developed ex many clinical trials have examined the effect of diverse pro- vivo screening system to identify immunoregulatory pro- biotic strains on the modulation of IBD progression including biotics that induce high levels of IL-10 and Foxp3+ Treg while LGG (78) and E. coli strain Nissle 1917 (79,80). In addition, reducing pro-inflammatory cytokines. We are currently under VSL#3, a mixture of 4 lactobacilli strains (Lactobacillus planta- investigation to identify potent immunoregulatory probiotics rum, Lactobacillus casei, Lactobacillus acidophilus, Lactoba- from the traditional Korean fermented foods using the ex vivo cillus delbrueckii ssp. bulgaricus), 3 bifidobacteria strains screening system. (Bifidobacterium infantis, Bifidobacterium breve, Bifidobacte- The role of probiotics in inflammatory bowel disease rium longum), and 1 strain of Streptococcus (Streptococcus (IBD): Inflammatory bowel disease (IBD) is characterized by salivarius ssp. thermophilus), has been examined in ulcerative a chronic dysregulation of the immune response in the gastro- colitis (UC), Crohn's disease (CD) (81,82). The therapeutic ef- intestinal tract (GI tract). Proinflammatory cytokines such as fects of several probiotic strains in animal studies and clinical INF-γ, TNF-α, IL-6 and IL-1β are major pathogenic cyto- trials were summarized in Table I and Table II, respectively. kines but the pathogenesis is still not clear (75). Recently Several studies have investigated the influence of probiotic many studies have demonstrated that the GI tracts of patients consumption on colitis in animal trials. In particular, IL-10 with IBD are populated with increased levels of adherent and knockout mouse that develops IBD spontaneously has been pathogenic bacteria. Fecal numbers of anaerobic bacteria largely employed as a IBD model. Interestingly, IL-10 knock- such as Bacteroides species were greater while Lactobacilli out mice spontaneously develop colitis when colonized with and Bifidobacteria were fewer than in healthy control (76,77). a conventional flora but remain disease free when maintained

Table II. The role of probiotics in inflammatory bowel disease Study type Author (reference #) Probiotics Result Human Gupta (78) LGG Improved intestinal permeability Kruis (79) E. coli strain Nissle 1917 Similar relapse rates compared with patient on mesalazine, maintained remission Malchow (80) Maintained remission Gionchetti (81) VSL#3 Maintained remission Venturi (82) Maintained remission (UC) Mouse Madsen (86) Lactobaillus reuteri Attenuated colitis and improved mucosal barrier function O’Mahony (83) Lactobacillus Reduced incidence of salivarious UCC118 mucosal inflammation, modulated fecal flora Sheil (85) Modulated inflammatory cytokine response in the Peyer’s patch Schultz (87) Lactobacillus Attenuated onset of disease, salivarious UCC118, Bifi- modulated gut flora, reduced in vitro production of dobacterium infantis IFN-γ, TNF-α, IL-12 Sheil (84) Bifidobacterium infantis Attenuated colitis, reduced IL-12 and INF-γ production by mesenteric lymph node

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under germ-free conditions (83-87). These studies suggest the 2002. Probiotics and atopic dermatitis. A new strategy in role of commensal flora in the development of inflammatory atopic dermatitis. Dig. Liver Dis. 34 Suppl 2: S68-71. 4. Sheil, B., F. Shanahan, and L. O'Mahony. 2007. Probiotic ef- bowel disease. The role of probiotic strains in animal model fects on inflammatory bowel disease. J. Nutr. 137(3 Suppl of IBD was summarized in Table II. 2): 819S-824S. Collectively these studies indicate that although the pro- 5. Leung, D. Y., M. Boguniewicz, M. D. Howell, I. Nomura, biotic administration has potential therapeutic efficacy in IBD, and Q. A. Hamid. 2004. New insights into atopic dermatitis. J. Clin. Invest. 113: 651-657. larger controlled trials are necessary before the use of pro- 6. Leung, D. Y., N. Jain, and H. L. Leo. 2003. New concepts biotics as a routine medical treatment. in the pathogenesis of atopic dermatitis. Curr. Opin. Immunol. 15: 634-638. 7. Okada, H., C. 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The human microbiome for Agricultural Science & Technology Development (Project project. Nature 449: 804-810. 15. Human Microbiome Jumpstart Reference Strains Consortium, No.: PJ907153), National Academy of Agricultural Science, K. E. Nelson, G. M. Weinstock, S. K. Highlander, K. C. Rural Development Administration, Republic of Korea, and by Worley, H. H. Creasy, J. R. Wortman, D. B. Rusch, M. a grant from Korea Food Research Institute. Mitreva, E. Sodergren, A. T. Chinwalla, M. Feldgarden, D. Gevers, B. J. Haas, R. Madupu, D. V. Ward, B. W. Birren, R. A. Gibbs, B. Methe, J. F. Petrosino, R. L. Strausberg, G. CONFLICTS OF INTEREST G. Sutton, O. R. White, R. K. Wilson, S. Durkin, M. G. Giglio, S. Gujja, C. Howarth, C. D. Kodira, N. Kyrpides, T. Mehta, D. M. Muzny, M. Pearson, K. Pepin, A. Pati, X. Qin, The authors have no financial conflict of interest. C. Yandava, Q. Zeng, L. Zhang, A. M. Berlin, L. Chen, T. A. Hepburn, J. Johnson, J. McCorrison, J. Miller, P. Minx, C. 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